Pituitary and Hypothalamic Disorders
Physiology
Growth
Hormone
is a 191-amino acid peptide. Secretion is
stimulated by two hypothalamic
growth hormone-releasing hormones and inhibited by the hypothalamic
tetradecapeptide somatostatin. GH binds to receptors in the liver and induces insulin-like
growth factor 1, which mediates most of the growth-promoting effects of the
growth hormone.
Prolactin
has 198 amino acids. Its secretion is under inhibitory
control by hypothalamic dopamine. TRH and vasoactive intestinal polypeptide
(VIP) are prolactin-releasing factors. Prolactin levels increase during
pregnancy, enhancing breast development. Postpartum prolactin stimulates milk
production.
Evaluation of prolactin reserve: prolactin levels
increase 3 to 5fold 15 to 30 minutes after TRH administration (200 µg i.v.)
Thyroid-stimulating
hormone (TSH)
28,000 dalton glycoprotein hormone. TSH secretion
is stimulated by the hypothalamic tripeptide TRH. Negative feedback inhibition of TSH secretion by peripheral
thyroid hormones.
Adrenocorticotropic
Hormone (ACTH)
A 39-amino acid peptide.
Hypothalamic corticotropin-releasing hormone (CRH) stimulates ACTH secretion.
Cortisol exerts a negative feedback effect on ACTH and CRH.
Gonadotropins
(LH and FSH)
Hypothalamic GnRH regulates LH and FSH secretion. Gonadal steroids
exert both positive and negative feedback effects on gonadotroph secretion. LH
stimulates gonadal steroid secretion by testicular Leydig cells and by the
ovarian follicles. In females, the ovulatory LH surge results in rupture of the
follicle and then luteinization. In males, FSH stimulates Sertoli cell
spermatogenesis, and in females, follicular development.
Pituitary adenomas
Clin: headache, visual loss (typically bitemporal
hemianopia), syndromes of hypopituitary hormone hypersecretion and
hyposecretion, and incidentally discovered sellar enlargement.
Hypothalamic
dysfunction
In children and young adults, craniopharyngioma is
the most frequent cause of hypothalamic dysfunction.
Clin: visual loss, symptoms of raised intracranial
pressure {headache and vomiting), hypopituitarism including growth failure, and
diabetes insipidus.
Hypothalamic disturbances: disorders of thirst
(dehydration or polydipsia and polyuria), appetite (hyperphagia and obesity),
temperature regulation, behaviour, and consciousness (somnolence and emotional
lability).
Craniopharyngeoma is treated primarily with
surgical resection and then radiotherapy.
Hypopituitarism
results from diminished secretion of one or more
pituitary hormones. Pituitary insufficiency is usually a slow, insidious
disorder.
Growth
Hormone Deficiency
during infancy and childhood growth retardation, short stature, and
fasting hypoglycemia.
In adults: increased abdominal adiposity, reduced
strength and exercise capacity, cold intolerance, impaired psycho-social
well-being. Adult GH deficiency is usually accompanied by other symptoms of
panhypopituitarism.
TSH
deficiency
causes thyroid gland involution and hypofunction.
Clin: lethargy, constipation, cold intolerance,
bradycardia, weight gain, dry skin, poor appetite, and delayed reflex
relaxation time.
Dg: low TSH + low T4 and T3
Etiology of hypopituitarism
type of disorder
congenital septo-optic
dysplasia
Prader-Willi
syndrome
Lawrence-Moon-Biedle
syndrome
isolated anterior
pituitary hormone or RF deficiency
tumors pituitary
secretory
adenomas
nonsecretory
adenomas
hypothalamic
craniopharyngioma
hamartoma
pinealoma
dermoid
epidermoid
glioma
lymphoma
meningioma
immunological autoimmune
lymphocytic hypophysitis
infiltrative hemochromatosis
Langerhans
cell histiocytosis
sarcoidosis
metastatic
carcinoma
amyloidosis
infectious tuberculosis
mycoses
syphilis
physical trauma cranial
trauma and hemorrhage
ionizing
radiation
stalk
section
surgery
vascular postpartum
pituitary necrosis (Sheehan's syndrome)
pituitary
apoplexy
carotid
aneurysm
Gonadotropin
deficiency
Central hypogonadism in childhood results in
failure to enter normal puberty. Females have delayed breast development, scant
pubic and axillary hair, and primary amenorrhea. In boys, the phallus and
testes remain small, and body hair is sparse.
Sex steroids are required for closure of the
epiphyses of the long bones.
Clin: tall adolescents with eunuchoid proportions. In adult women,
hypogonadism presents as breast atrophy, loss of pubic and axillary hair, and
secondary amenorrhea. Hypogonadal adult males develop testicular atrophy,
decreased libido, impotence, and loss of body hair.
ADH
(vasopressin) deficiency
occurs with posterior pituitary dysfunction and
leads to DI with polyuria, polydipsia, and nocturia.
Dg of
pituitary hormone deficiency
Quadruple Bolus Test for
Anterior Pituitary Reserve
hypothalamic releasing hormone pituitary
hormone
TRH 200 µg TSH,
prolactin
CRF 1 µg/kg ACTH
GHRH 1 µg/kg GH
gonadotropin RH 100 µg FSH,
LH
Th of panhypopituitarism
replacement of thyroxine, glucocorticoids, and sex
steroids. Children with short stature should receive GH replacement therapy.
Testosterone therapy in males restores libido and potency, beard growth, and
muscle strength.
Estrogen replacement therapy in females maintains
secondary sex characteristics and prevents hot flashes. Human menopausal
gonadotropins and human chorionic gonadotropin given i.m. or gonadotropin RH
administered by infusion pumps may be given to induce ovulation.
In patients with combined TSH and ACTH deficiency,
glucocorticoids should be replaced prior to thyroxine, as thyroxine may
precipitate acute adrenal failure.
Empty
Sella Syndrome
occurs when the arachnoid membranes herniate
through an incompetent diaphragma sella and extend into the sella turcica,
partially filling it with cerebrospinal fluid and compressing the pituitary
gland. Primary empty sella syndrome is the most common cause of an
enlarged sella turcica. This results from a congenital weakness in the
diaphragma sella.
Secondary empty sella syndrome can occur following pituitary surgery or radiation therapy or in Sheehan's
syndrome. Empty sella syndrome is
usually asymptomatic and detected incidentally on routine imaging of the head.
Endocrine function is usually normal; partial hypopituitarism may be present.
Dg: MRI - fluid in sella turcica
Pituitary
tumours
Prolactinomas are the most common secretory
pituitary tumours.
Secretory pituitary tumours: signs and symptoms
due to hypersecretion of the
particular pituitary trophic hormone.
GH adenomas: acromegaly, prolactinomas: amenorrhoea + galactorrhea in females and sexual dysfunction
in males, ACTH-secreting adenomas:
Cushing disease.
Large pituitary adenomas (secretory or
nonsecretory) can result in signs and symptoms due to pressure on surrounding
structures. Headache is a frequent symptom. Extension of the tumour into the
suprasellar space ® compression of the
optic chiasm bitemporal
hemianopia. Lateral extension into the cavernous sinus can result in
ophthalmoplegia, diplopia, or ptosis due to dysfunction of the third, fourth,
fifth, and sixth cranial nerves. Compression of surrounding normal pituitary
tissue due to an enlarging tumor mass can cause hyposecretion of one or several
pituitary trophic hormones.
Destructive pituitary lesions result in hormone
loss in the following pattern: GH - LH/FSH - TSH - ACTH - prolactin.
Prolactinomas
Hyperprolactinemia in women: hypogonadism ® estrogen deficiency. Gonadotropin levels are normal, and sex
steroids are decreased. Prolactin inhibits pulsatility in gonadotropin
secretion ® anovulation. In
hyperprolactinemic males, testosterone levels are usually suppressed.
Clin: in women, amenorrhea, galactorrhea, and
infertility. Estrogen deficiency may cause osteopenia, vaginal dryness, hot
flashes, and irritability. Prolactin stimulates adrenal androgen production ® weight gain and hirsutism.
Males usually present with loss of libido and
impotence due to hypogonadism.
Dg: basal serum prolactin level > 200 ng/ml;
MRI.
Th: bromocriptine (a dopamine agonist) at a dosage
of 2.5 to 15 mg/day orally in divided doses restores gonadal function and
fertility in a majority of patients. Bromocriptine may cause tumour shrinkage.
Surgery is indicated in patients with visual field abnormalities or neurologic
symptoms. Trans-sphenoidal microsurgery is the procedure of choice.
Acromegaly
and gigantism
In childhood, hypersecretion of GH leads to
gigantism, in adults
acromegaly (local overgrowth of bone in the acral areas).
Clin: acral enlargement - widening of the hand and
feet and coarsening of the facial features. The mandible grows downward and forward ® prognathism and widely spaced teeth. Ring, glove, and shoe size increase.
Dg: insulin-like growth factor-1 mediates the
classical acral changes that occur with acromegaly. IGF-1 levels are elevated.
GH levels 2 hours after an oral glucose load of
100g. In healthy persons, GH levels are suppressed to < 2 ng/ml.
MRI or CT of the pituitary
Th: trans-sphenoidal microsurgery is the treatment
of choice. Radiotherapy has a high incidence of hypopituitarims.
Medical management: bromocriptine (effective only
in a minority of patients) and octreotide (a long-acting somatostatin analogue
- very effective). It is administered as a s.c. injection three times daily.
Clinical
features of acromegaly
type of change change manifestation
somatic acral
changes enlarged
hands and feet
musculoskeletal arthralgias
changes prognathism
carpal
tunnel syndrome
proximal
myopathy
skin
changes sweating
colon
changes polyps
carcinoma
cardiovascular cardiomegaly
hypertension
visceromegaly tongue
thyroid
liver
endocrine reproduction
menstrual
abnormalities
problems galactorrhea
decreased
libido
carbohydrate
impaired
glucose tolerance
metabolism diabetes
mellitus
lipid
metabolism hypertriglyceridemia
Gonadotropin-Secreting
Pituitary Tumours
Mainly in males, are rare. Secrete usually FSH
only.
Clin:
·
signs of local pressure (visual
impairment);
·
hypogonadism
Th: surgical removal ± subsequent radiotherapy
Thyrotropin-Secreting
Pituitary Tumour
Extremely rare
Dg: increased TSH + increased T4
Th: surgery + radiotherapy
The
Posterior Pituitary Gland
ADH is a 1084-dalton nonapeptide. It binds to
receptors on the renal tubule, increasing the water permeability of the luminal
membrane of the collecting duct epithelium, thus facilitating reabsorption of
water. Maximal ADH effect results in a small volume of concentrated urine with
osmolarity as high as 1200 mOsm/kg. Deficiency of ADH results in a large volume
of very dilute urine (as low as 100 mOsm/kg).
ADH also binds to peripheral arteriolar receptors,
causing vasoconstriction and increase in blood pressure; however, it
also causes bradycardia and inhibition of sympathetic nerve activity.
Deficiency of ADH or insensitivity of the kidney
to ADH ® diabetes insipidus manifested
as polyuria and polydipsia. Inappropriate secretion of ADH ® the syndrome of inappropriate
ADH secretion (SIADH) ® a hyponatremic state.
Oxytocin is a 1007-dalton nonapeptide that causes uterine smooth muscle
contraction. It is released by
nipple stimulation and facilitates milk ejection by causing mammary duct
myoepithelial cell contraction in response to nipple stimulation.
Diabetes
Insipidus
Central (neurogenic) or renal (nephrogenic).
Patients are polyuric, secreting large volumes of
diluted urine
dehydration ® thirst ® polydipsia.
Causes of Diabetes Insipidus
Causes
of Central Diabetes Insipidus
·
idiopathic
·
familial
·
hypophysectomy
·
infiltration of hypothalamus
and posterior pituitary
·
Langerhans cell histiocytosis
·
granulomas
·
infection
·
tumors
·
autoimmune
Causes
of nephrogenic diabetes insipidus
·
idiopathic
·
familial
·
chronic renal disease
(pyelonephritis, polycystosis)
·
hypokalemia
·
hypercalcemia
·
sickle cell anemia
·
drugs
lithium
fluoride
demeclocycline
colchicine
DD: primary polydipsia ® decreased ADH secretion ® water diuresis. Random simultaneous
samples of plasma and urine for sodium and osmolarity: in diabetes insipidus, urine osmolarity
< plasma osmolarity. Plasma osmolarity may be elevated, depending on the
patient's state of hydration. In primary polydipsia, both plasma and urine are
dilute.
The water deprivation test: the patient is denied fluids for 12 to 18 hours, and body weight, blood
pressure, urine volume, urine specific gravity, and plasma and urine osmolarity
are measured every 2 hours. If the body weight falls more than 3%, the study
should be terminated. A normal
response is a decrease in urine output to 0.5 ml/min, as well as an increase in
urine concentration to greater than that of plasma. Patients with DI maintain a
high urine output, which continues to be dilute (specific gravity < 1.005
{200 mOsm/kg of water}). Patients with primary polydipsia increase their urine
osmolarity to values > plasma osmolarity. Water deprivation is continued
until the urine osmolarity plateaus (an hourly increase of < 30 mOsm/kg for
three successive hours). At that point, 5 µg of vasopressin is administered s.c., and the urine osmolarity
is measured after 1 hour. Patients with complete central DI increase urine
osmolarity above plasma osmolarity, whereas in nephrogenic DI the urine
osmolarity increases less than 50%. Patients with primary polydipsia have
increases < 10%.
Th: central DI - desmopressin acetate (DDAVP), a
synthetic analog of ADH, is administered intranasally. Adequacy of replacement
is monitored by serum osmolarity and sodium.
Nephrogenic
DI
As far as possible, the underlying disease process
should be reversed. Diuretics with
dietary salt restriction can be used.
SIADH
Plasma ADH concentrations are inappropriately high for plasma
osmolarity, resulting in water retention leading to hyponatremia and decreased
plasma osmolarity (< 280 mOsm/kg). Urine osmolarity is higher than the
plasma osmolarity.
Disorders Associated with SIADH
type of disorder disorder
pulmonary disorders malignant
(oat cell carcinoma)
benign
(TBC, pneumonia, abscess)
CNS disorders meningitis
brain
abscess
head
trauma
adverse drug effects clofibrate
chlorpropamide
cyclophosphamide
phenothiazine
carbamazepine
tumours (ectopic lymphoma
production of ADH) sarcoma
carcinoma
of pancreas or duodenum
Th: the underlying condition should be treated.
Fluid restriction is the cornerstone of treatment.
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